ABSTRACT
Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-ß peptide (Aß) aggregates. We used Caenorhabditis elegans that express Aß in muscle cells as a model of IBM, with the aim of analyzing Aß-induced muscle pathology and evaluating the consequences of modulating Aß aggregation. First, we tested whether the altered motility we observed in the Aß transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents. Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases Aß oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays Aß-induced paralysis. Our results indicate that copper modulates Aß-induced pathology and suggest that Aß oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.
Subject(s)
Amyloid beta-Peptides/metabolism , Copper/therapeutic use , Myositis, Inclusion Body/drug therapy , Neuromuscular Junction/drug effects , Animals , Animals, Genetically Modified , Caenorhabditis elegans , Copper/administration & dosage , Copper/metabolism , Disease Models, Animal , Myositis, Inclusion Body/metabolism , Myositis, Inclusion Body/pathology , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathologyABSTRACT
Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer's disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM.
Subject(s)
Caenorhabditis elegans/anatomy & histology , Disease Models, Animal , Muscles , Myositis, Inclusion Body , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Caenorhabditis elegans/genetics , Humans , Metals/metabolism , Mitochondria/metabolism , Muscles/metabolism , Muscles/pathology , Myositis, Inclusion Body/metabolism , Myositis, Inclusion Body/pathology , Oxidative Stress , Peptides/genetics , Peptides/metabolism , RNA InterferenceABSTRACT
To assess the differential expression of adhesion molecules ICAM-1 and VCAM-1 in vessels and muscle fibers in acquired inflammatory myopathy, a series comprising thirty-seven muscle biopsy specimens from patients with JDM, fifteen with DM, fifteen with PM and seven with IBM was studied. Histochemical and immunohistochemical tests (StreptABCcomplex/HRP) for ICAM-1 and VCAM-1 (Dakopatts) were performed in serial frozen sections. ICAM-1 expression in vessels was significantly (p<0.0001) more present in JDM than PM, DM or IBM. However, in muscle fibers, ICAM-1 expression was absent in both JDM and IBM, but present in 33.4% and 40% in PM and DM respectively (p<0.0001). VCAM-1 expression in vessels was significantly more present in PM and DM than JDM and IBM (p<0.0001) while VCAM-1 expression in muscle fibers was almost absent in the four groups (p=0.2632). These findings emphasize the importance of adhesion molecules in the pathophysiology of the inflammatory myopathies, mainly the marked ICAM-1 expression in vessels in JDM, corroborating the microvascular involvement in this disease. In contrast, VCAM-1 seems not to play a major role in JDM, as previously described in PM, DM and IBM. Adhesion molecule expression in JDM presents a differential characteristic when compared to PM, DM and IBM.